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1.
Cell ; 185(23): 4428-4447.e28, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36318921

RESUMO

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.


Assuntos
Neurogênese , Organoides , Gravidez , Feminino , Humanos , Adulto , Cromatina , Córtex Pré-Frontal , Análise de Célula Única , Redes Reguladoras de Genes
2.
Cell ; 172(5): 1122-1131.e9, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474911

RESUMO

The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.


Assuntos
Aprendizado Profundo , Diagnóstico por Imagem , Pneumonia/diagnóstico , Criança , Humanos , Redes Neurais de Computação , Pneumonia/diagnóstico por imagem , Curva ROC , Reprodutibilidade dos Testes , Tomografia de Coerência Óptica
3.
Nucleic Acids Res ; 52(D1): D929-D937, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37831137

RESUMO

DNA methylation acts as a vital epigenetic regulatory mechanism involved in controlling gene expression. Advances in sequencing technologies have enabled characterization of methylation patterns at single-base resolution using bisulfite sequencing approaches. However, existing methylation databases have primarily focused on mean methylation levels, overlooking phased methylation patterns. The methylation status of CpGs on individual sequencing reads represents discrete DNA methylation haplotypes (mHaps). Here, we present mHapBrowser, a comprehensive database for visualizing and analyzing mHaps. We systematically processed data of diverse tissues in human, mouse and rat from public repositories, generating mHap format files for 6366 samples. mHapBrowser enables users to visualize eight mHap metrics across the genome through an integrated WashU Epigenome Browser. It also provides an online server for comparing mHap patterns across samples. Additionally, mHap files for all samples can be downloaded to facilitate local processing using downstream analysis toolkits. The utilities of mHapBrowser were demonstrated through three case studies: (i) mHap patterns are associated with gene expression; (ii) changes in mHap patterns independent of mean methylation correlate with differential expression between lung cancer subtypes; and (iii) the mHap metric MHL outperforms mean methylation for classifying tumor and normal samples from cell-free DNA. The database is freely accessible at http://mhap.sibcb.ac.cn/.


Assuntos
Metilação de DNA , Bases de Dados Genéticas , Animais , Humanos , Camundongos , Ratos , Epigênese Genética , Haplótipos , Análise de Sequência de DNA
4.
Plant J ; 118(5): 1413-1422, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38341804

RESUMO

Mung bean (Vigna radiata) stands as a crucial legume crop in Asia, contributing to food security. However, our understanding of the underlying genetic foundation governing domesticated agronomic traits, especially those linked to pod architecture, remains largely unexplored. In this study, we delved into the genomic divergence between wild and domesticated mung bean varieties, leveraging germplasm obtained from diverse sources. Our findings unveiled pronounced variation in promoter regions (35%) between the two mung bean subpopulations, suggesting substantial changes in gene expression patterns during domestication. Leveraging transcriptome analysis using distinct reproductive stage pods and subpopulations, we identified candidate genes responsible for pod and seed architecture development, along with Genome-Wide Association Studies (GWAS) and Quantitative Trait Locus (QTL) analysis. Notably, our research conclusively confirmed PDH1 as a parallel domesticated gene governing pod dehiscence in legumes. This study imparts valuable insights into the genetic underpinnings of domesticated agronomic traits in mung bean, and simultaneously highlighting the parallel domestication of pivotal traits within the realm of legume crops.


Assuntos
Produtos Agrícolas , Domesticação , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Vigna , Vigna/genética , Locos de Características Quantitativas/genética , Produtos Agrícolas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Sementes/genética , Genoma de Planta/genética , Regulação da Expressão Gênica de Plantas , Genômica , Fenótipo
5.
Artigo em Inglês | MEDLINE | ID: mdl-38592427

RESUMO

The current CAR-T cell therapy products have been hampered in their druggability due to the personalized preparation required, unclear pharmacokinetic characteristics, and unpredictable adverse reactions. Enabling standardized manufacturing and having clear efficacy and pharmacokinetic characteristics are prerequisites for ensuring the effective practicality of CAR-T cell therapy drugs. This review provides a broad overview of the different approaches for controlling behaviors of CAR-T cells in vivo. The utilization of genetically modified vectors enables in vivo production of CAR-T cells, thereby abbreviating or skipping the lengthy in vitro expansion process. By equipping CAR-T cells with intricately designed control elements, using molecule switches or small-molecule inhibitors, the control of CAR-T cell activity can be achieved. Moreover, the on-off control of CAR-T cell activity would yield potential gains in phenotypic remodeling. These methods provide beneficial references for the future development of safe, controllable, convenient, and suitable for standardized production of CAR-T cell therapy products.

6.
Methods ; 226: 151-160, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38670416

RESUMO

Chromatin loop is of crucial importance for the regulation of gene transcription. Cohesin is a type of chromatin-associated protein that mediates the interaction of chromatin through the loop extrusion. Cohesin-mediated chromatin interactions have strong cell-type specificity, posing a challenge for predicting chromatin loops. Existing computational methods perform poorly in predicting cell-type-specific chromatin loops. To address this issue, we propose a random forest model to predict cell-type-specific cohesin-mediated chromatin loops based on chromatin states identified by ChromHMM and the occupancy of related factors. Our results show that chromatin state is responsible for cell-type-specificity of loops. Using only chromatin states as features, the model achieved high accuracy in predicting cell-type-specific loops between two cell types and can be applied to different cell types. Furthermore, when chromatin states are combined with the occurrence frequency of CTCF, RAD21, YY1, and H3K27ac ChIP-seq peaks, more accurate prediction can be achieved. Our feature extraction method provides novel insights into predicting cell-type-specific chromatin loops and reveals the relationship between chromatin state and chromatin loop formation.


Assuntos
Fator de Ligação a CCCTC , Proteínas de Ciclo Celular , Cromatina , Proteínas Cromossômicas não Histona , Coesinas , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Cromatina/metabolismo , Cromatina/genética , Humanos , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Fator de Transcrição YY1/metabolismo , Fator de Transcrição YY1/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Biologia Computacional/métodos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Histonas/metabolismo , Histonas/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Sequenciamento de Cromatina por Imunoprecipitação/métodos
7.
Lab Invest ; 104(6): 102059, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38615731

RESUMO

High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.


Assuntos
Adenosina , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Neoplasias Ovarianas , Receptores de Superfície Celular , Animais , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/secundário , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Receptores de Superfície Celular/genética
8.
EMBO J ; 39(19): e104063, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32790115

RESUMO

The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.


Assuntos
Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Humanos , RNA-Seq , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Neoplasias de Mama Triplo Negativas/patologia
9.
BMC Cancer ; 24(1): 119, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38263004

RESUMO

BACKGROUND: Adoptive cell therapy has achieved great success in treating hematological malignancies. However, the production of chimeric antigen receptor T (CAR-T) cell therapy still faces various difficulties. Natural killer (NK)-92 is a continuously expandable cell line and provides a promising alternative for patient's own immune cells. METHODS: We established CAR-NK cells by co-expressing natural killer group 2 member D (NKG2D) and IL-21, and evaluated the efficacy of NKG2D-IL-21 CAR-NK cells in treating lung cancer in vitro and in vivo. RESULTS: Our data suggested that the expression of IL-21 effectively increased the cytotoxicity of NKG2D CAR-NK cells against lung cancer cells in a dose-dependent manner and suppressed tumor growth in vitro and in vivo. In addition, the proliferation of NKG2D-IL-21 CAR-NK cells were enhanced while the apoptosis and exhaustion of these cells were suppressed. Mechanistically, IL-21-mediated NKG2D CAR-NK cells function by activating AKT signaling pathway. CONCLUSION: Our findings provide a novel option for treating lung cancer using NKG2D-IL-21 CAR-NK cell therapy.


Assuntos
Interleucinas , Neoplasias Pulmonares , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Humanos , Imunoterapia Adotiva , Terapia Baseada em Transplante de Células e Tecidos
10.
Arch Microbiol ; 206(5): 235, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722413

RESUMO

In recent years, blueberry root rot has been caused mainly by Fusarium commune, and there is an urgent need for a green and efficient method to control this disease. To date, research on Schizophyllum commune has focused on antioxidant mechanisms, reactive dye degradation, etc., but the mechanism underlying the inhibition of pathogenic microorganisms is still unclear. Here, the control effects of S. commune on F. commune and blueberry root rot were studied using adversarial culture, tissue culture, and greenhouse pot experiments. The results showed that S. commune can dissolve insoluble phosphorus and secrete various extracellular hydrolases. The results of hyphal confrontation and fermentation broth antagonism experiments showed that S. commune had a significant inhibitory effect on F. commune, with inhibition rates of 70.30% and 22.86%, respectively. Microscopy results showed distortion of F. commune hyphae, indicating that S. commune is strongly parasitic. S. commune had a significant growth-promoting effect on blueberry tissue-cultured seedlings. After inoculation with S. commune, inoculation with the pathogenic fungus, or inoculation at a later time, the strain significantly reduced the root rot disease index in the potted blueberry seedlings, with relative control effects of 79.14% and 62.57%, respectively. In addition, S. commune G18 significantly increased the antioxidant enzyme contents in the aboveground and underground parts of potted blueberry seedlings. We can conclude that S. commune is a potential biocontrol agent that can be used to effectively control blueberry root rot caused by F. commune in the field.


Assuntos
Mirtilos Azuis (Planta) , Fusarium , Doenças das Plantas , Raízes de Plantas , Schizophyllum , Mirtilos Azuis (Planta)/microbiologia , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Raízes de Plantas/microbiologia , Fusarium/fisiologia , Schizophyllum/metabolismo , Schizophyllum/crescimento & desenvolvimento , Antibiose , Hifas/crescimento & desenvolvimento , Agentes de Controle Biológico , Plântula/microbiologia , Plântula/crescimento & desenvolvimento
11.
Arch Microbiol ; 206(2): 86, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302781

RESUMO

Dark septate endophytes (DSEs) inhabit plant roots and soil in ecosystems and host plants worldwide. DSE colonization is influenced by cultivars, soil factors, and specific habitat conditions. The regular diversity of DSEs in blueberries in Guizhou, China, is still unclear. In this study, four cultivars (Gardenblue, Powderblue, O'Neal, and Legacy) in three areas (Gaopo, Majiang, and Fenggang) in Guizhou were used to identify DSEs by morphological and molecular biological methods and to clarify the relationship between DSE diversity and DSE colonization and soil factors of cultivated blueberries in Guizhou. The DSEs isolated from cultivated blueberry roots in 3 areas in Guizhou Province were different, belonging to 17 genera, and the dominant genera were Penicillium, Phialocephala, and Thozetella. DSEs isolated from Majiang belonged to 12 genera and 16 species, those from Gaopo belonged to 7 genera and 15 species, and those from Fenggang belonged to 5 genera and 7 species. Among the different blueberry varieties, 11 genera were isolated from O'Neal, 12 genera were isolated from Powderblue, 11 genera were isolated from Legacy and 13 genera were isolated from Gardenblue. Coniochaeta is endemic to O'Neal, Chaetomium and Curvularia are endemic to Powderblue, and Thielavia is endemic to Legacy. Correlation analysis showed that DSE diversity was significantly correlated with DSE colonization and soil factors.


Assuntos
Ascomicetos , Mirtilos Azuis (Planta) , Micorrizas , Ecossistema , Solo , Raízes de Plantas/microbiologia , Endófitos/genética
12.
Pharmacol Res ; 204: 107221, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38768669

RESUMO

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Imunoterapia Adotiva , Humanos , Animais , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Camundongos Nus , Camundongos Endogâmicos BALB C , Camundongos , Feminino
13.
Faraday Discuss ; 249(0): 181-194, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-37791622

RESUMO

The nanoconfinement of water can result in dramatic differences in its physical and chemical properties compared to bulk water. However, a detailed molecular-level understanding of these properties is still lacking. Vibrational spectroscopy, such as Raman and infrared, is a popular experimental tool for studying the structure and dynamics of water, and is often complemented by atomistic simulations to interpret experimental spectra, but there have been few theoretical spectroscopy studies of nanoconfined water using first-principles methods at ambient conditions, let alone under extreme pressure-temperature conditions. Here, we compute the Raman and IR spectra of water nanoconfined by graphene at ambient and extreme pressure-temperature conditions using ab initio simulations. Our results revealed alterations in the Raman stretching and low-frequency bands due to the graphene confinement. We also found spectroscopic evidence indicating that nanoconfinement considerably changes the tetrahedral hydrogen bond network, which is typically found in bulk water. Furthermore, we observed an unusual bending band in the Raman spectrum at ∼10 GPa and 1000 K, which is attributed to the unique molecular structure of confined ionic water. Additionally, we found that at ∼20 GPa and 1000 K, confined water transformed into a superionic fluid, making it challenging to identify the IR stretching band. Finally, we computed the ionic conductivity of confined water in the ionic and superionic phases. Our results highlight the efficacy of Raman and IR spectroscopy in studying the structure and dynamics of nanoconfined water in a large pressure-temperature range. Our predicted Raman and IR spectra can serve as a valuable guide for future experiments.

14.
Bioorg Med Chem Lett ; 99: 129613, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38224754

RESUMO

A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0-100 µM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.


Assuntos
Antineoplásicos , Isatina , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Isatina/química , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Proliferação de Células , Relação Estrutura-Atividade , Estrutura Molecular
15.
Environ Sci Technol ; 58(14): 6370-6380, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38497719

RESUMO

The discovery of the significant lethal impacts of the tire additive transformation product N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) on coho salmon has garnered global attention. However, the bioaccumulation and trophic transfer of tire additives and their transformation products (TATPs) within food webs remain obscure. This study first characterized the levels and compositions of 15 TATPs in the Pearl River Estuary, estimated their bioaccumulation and trophic transfer potential in 21 estuarine species, and identified priority contaminants. Our observations indicated that TATPs were prevalent in the estuarine environment. Eight, six, seven, and 10 TATPs were first quantified in the shrimp, sea cucumber, snail, and fish samples, with total mean levels of 45, 56, 64, and 67 ng/g (wet weight), respectively. N,N'-Diphenyl-p-phenylenediamine (DPPD) and N,N'-bis(2-methylphenyl)-1,4-benzenediamine (DTPD) exhibited high bioaccumulation. Significant biodilution was only identified for benzothiazole, while DPPD and DTPD displayed biomagnification trends based on Monte Carlo simulations. The mechanisms of bioaccumulation and trophodynamics of TATPs could be explained by their chemical hydrophobicity, molecular mass, and metabolic rates. Based on a multicriteria scoring technique, DPPD, DTPD, and 6PPD-Q were characterized as priority contaminants. This work emphasizes the importance of biomonitoring, particularly for specific hydrophobic tire additives.


Assuntos
Cadeia Alimentar , Fenilenodiaminas , Poluentes Químicos da Água , Animais , Bioacumulação , Monitoramento Ambiental , Poluentes Químicos da Água/análise
16.
Acta Pharmacol Sin ; 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641746

RESUMO

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

17.
BMC Palliat Care ; 23(1): 24, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273273

RESUMO

OBJECTIVE: This study aims to investigate the experiences of parents who have experienced bereavement in their efforts to preserve memories of their deceased child. METHODS: Employing a qualitative meta-synthesis approach, this study systematically sought relevant qualitative literature by conducting searches across various electronic databases, including PubMed, Embase, CINAHL, PsycINFO, Web of Science, Cochrane Library, and Wiley, up until July 2023. RESULTS: Nine studies are eligible for inclusion and included in the meta-synthesis. Three overarching categories are identified: (1) Affirming the Significance of Memory Making. (2) Best Practices in Memory Making. (3) Barriers to Effective Memory Making. CONCLUSION: Bereaved parents highly value the act of creating lasting memories, emphasizing its profound significance. While forming these memories, it is imperative to offer family-centered care and honor diverse preferences and needs. It is essential to offer effective support to parents, offering them a range of choices. Furthermore, a more comprehensive examination of memory-making practices is required to better understand their influence on parents' recollections of their deceased child.


Assuntos
Luto , Criança , Humanos , Pesar , Pais , Pesquisa Qualitativa
18.
BMC Oral Health ; 24(1): 179, 2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38311720

RESUMO

OBJECTIVE: To clarify whether the 3D printing model has auxiliary functions in toto extraction of donor tooth in autotransplantation cases. METHODS: Two hundred and sixty patients who would have operation of ATT were divided into two groups. In group 1, determination of the tooth extraction in toto was predicted only according to the clinical and imaging examination. In group 2, the prediction was performed according to the clinical and imaging examination as well as the 3D model of donor tooth pre-extraction. A prespctive clinical study was designed on intra-group comparison between the predicted and actual donor teeth situation when extraction in cases of ATT. The consistent rate for the predicted results and the actual results were compared with the two groups. RESULTS: A remarkable difference was observed between the predicted results and the actual results of tooth positions and root numbers in group without model (p < 0,05). The consistency rate of the model group (94.62%) was significantly higher than that of non 3D model group (86.15%) (p = 0.034). CONCLUSION: The 3D printing model for the donor tooth is helpful for dentists to predict the accuracy of toto extraction of donor teeth in autotransplantation cases.


Assuntos
Compostos de Quinolínio , Cirurgia Assistida por Computador , Tiazóis , Dente , Humanos , Transplante Autólogo/métodos , Cirurgia Assistida por Computador/métodos , Extração Dentária , Impressão Tridimensional
19.
BMC Med ; 21(1): 40, 2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36737746

RESUMO

BACKGROUND: The ability of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to decrease certain microvascular events has called for the investigation of GLP-1 RAs against diabetic retinopathy (DR), but the evidence is limited. By combining data from observational and Mendelian randomization (MR) studies, we aimed to investigate whether GLP-1 RAs decrease the risk of DR. METHODS: We combined data from several Swedish Registers and identified patients with incident type 2 diabetes being treated with GLP-1 RAs between 2006 and 2015, and matched them to diabetic patients who did not use GLP-1 RAs as the comparisons. The Cox proportional hazards models were applied to assess the risk of DR. We further performed the summary-data-based MR (SMR) analyses based on the Genotype-Tissue Expression databases and the Genome-Wide Association Study of DR from the FinnGen consortium. RESULTS: A total of 2390 diabetic patients were treated with GLP-1 RAs and the incidence of DR was 5.97 per 1000 person-years. Compared with diabetic patients who did not use GLP-1 RAs having an incidence of 12.85 per 1000 person-years, the adjusted hazard ratio (HR) of DR was 0.42 [95% confidence interval (CI), 0.29-0.61]. Genetically-predicted GLP1R expression (the target of GLP-1 RAs) showed an inverse association with background [odds ratio (OR)=0.83, 95% CI, 0.71-0.97] and severe nonproliferative DR (OR=0.72, 95% CI, 0.53-0.98), and a non-significant association with overall (OR=0.97, 95% CI, 0.92-1.03) and proliferative DR (OR=0.98, 95% CI, 0.91-1.05). CONCLUSIONS: Both observational and mendelian randomization analyses showed a significantly lower risk of DR for patients treated with GLP-1 RAs, which calls for further studies to validate these findings.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/genética , Retinopatia Diabética/induzido quimicamente , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Peptídeo 1 Semelhante ao Glucagon
20.
Opt Express ; 31(15): 24939-24951, 2023 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-37475309

RESUMO

In the dispersive limit, the conventional photon blockade effect cannot be realized due to the absence of photon nonlinearity. We propose a scheme to recover the photon blockade effect of the dispersive Tavis-Cummings model, which makes it possible to realize the conventional photon blockade effect in the dispersive limit. It is shown that both single-photon and two-photon blockade effects can be recovered at appropriate qubit driving strength. The optimal qubit drive strength and cavity field drive detuning are given analytically. All analyses can be verified by numerical simulation, and the strongest photon blockade effect with the largest average photon number can be produced when the single excitation resonance condition is satisfied. Moreover, we find that the achieved two-photon blockade effect is relatively robust to thermal noise. Our proposal is able to obtain single-photon sources with high purity and high brightness and has great potential for applications in quantum communication processing.

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